Cardiovascular diseases associated with intravascular thrombosis are the most common cause of death in both developed and developing countries. Arterial and venous thromboses are the principal causes for the evolution of myocardial infarction, thromboembolic stroke and deep vein thrombosis. Approximately three million individuals die each year in the United States only from venous (deep vein thrombosis and pulmonary embolism) or arterial thrombosis (acute myocardial infarction and unstable angina).
Initiation of thrombosis is a complex process. The final event i.e. the thrombus formation, however, is primarily due to the activation of platelets and coagulation cascade. Clinical and experimental studies indicate that abnormalities in the normal blood flow, activation of platelets, coagulation cascade or fibrinolysis contribute to the pathogenesis of intravascular thrombosis/thromboembolism. Though the treatment strategy for thrombosis has improved with newer diagnostic and surgical tools but effective antithrombotic therapy with minimal side effects still poses a challenge to scientists around the globe.
Antithrombotic agents have been researched and developed for use in treating cardiovascular and other diseases. Presently established antithrombotic agents include heparin, coumarin, and aspirin. There are, however, limitations with these agents. For example, both heparin1 and coumarin2 have a highly-variable dose-related response, and their anticoagulant effects must be closely monitored to avoid a risk of serious bleeding. The erratic anticoagulant response of heparin is likely due to its propensity to bind non-specifically to plasma proteins. Aspirin has a limited efficacy and at high doses presents a risk of gastrointestinal bleeding.
Tissue plasminogen activators3,4, platelet GPIIb/IIIa antagonists5, ADP receptor antagonists6, are also being currently used to treat thrombosis, however, these drugs have some inherent problems and limitations. Therefore, new search is taken up to develop next generation anti-thrombotic agents such as direct thrombin inhibitors7, tissue factor pathway inhibitors8, Factor Xa inhibitors9, collagen antagonists10 and gene therapy. The search of a potent orally active and specific anti-thrombotic agent with minimal danger of bleeding or unrelated side effects is thus an area of interest. Moreover, the high cost of anticoagulant and antithrombotic therapy necessitates the search for efficacious new chemical entities.                1. Circulation 1998, 98, 1575-82.        2. Drugs 1994, 48, 185-97.        3. J Intern Med 1994, 236, 425-32.        4. J Antibiot 1996, 49, 1014-21.        5. Current Pharmaceutical Design 2003, 9(28) 2317-2322.        6. Current Pharmaceutical Design 2003, 9(28) 2303-2316.        7. Expert Opinion on Investigational Drugs 2004, 13(5) 465-477.        8. Drugs News and Perspective 2003, 16(6) 363-369.        9. Current Pharmaceutical Design 2003, 9(28) 2337-23247.        10. Drugs of the future 2003 28(1), 61-67.        